Despite advancements in treating ischemic heart disease (IIHD), the mortality and morbidity rates from this disease remain high. It is becoming increasingly recognized that psychosocial stress contributes to the development and course of IHD through various mechanisms. One such mechanism is thought to be stress induced physiological changes resulting in myocardial ischemia. Mental stress induced myocardial ischemia (MSIMI) is prevalent in patients with IHD.MSIMI is also clinically important as it has been shown to be associated with increased risk of poor prognosis, independent of conventional risk factors. The precise biochemical mechanisms underlying MSIMI are poorly known, but there is evidence that serotonergic dysregulation may play a role. Enhanced knowledge of the molecular basis of MSIMI will help inform the development of more effective pharmacotherapy for its treatment. This proposal takes advantage of existing data generated through NHLBI funded REMIT study that investigated the effect of selective serotonin reuptake inhibitor (SSRI) on MSIMI. As a part of the screening process, we collected demographic, psychometric data, cardiovascular responses to mental stress, and blood samples from 310 patients, and conducted a metabolomic pilot study in a subset of the population (30 patients with/without MSIMI [N=15/each]). Data revealed several strong metabolite differences between these groups of patients with/out MSIMI, the most prominent of which involved compounds from the tryptophan, tyrosine, and purine pathways. The proposed study will expand on the novel findings of this pilot study by profiling samples from the entire REMIT population using two complementary metabolomics platforms. An electrochemistry based platform, the one used in the pilot study, will be used to quantitate compounds from the tryptophan, tyrosine, purine, and sulphur amino acid pathways, areas of biochemistry that have been shown to be important in the study CNS mediated stress responses including MSIMI. We will also use a mass spectrometry based platform to profile compounds of intermediary metabolism including amino acids, fatty acids, acylcarnitines, and organic acids. This platform has been successfully applied to the study of cardiometabolic disease and has yielded insights into novel mechanisms of IHD. The output of these platforms will be used to identify and validate metabolomic profiles that: (a) that discriminate between patients with and without MSIMI (b) discriminate between patients showing a good or a poor response to escitalopram and (c) are associated with adverse events.